Molecular and structural traits of insulin receptor substrate 1/LC3 nuclear structures and their role in autophagy control and tumor cell survival

Adam Lassak, Mathew Dean, Dorota Wyczechowsk, Anna Wilk, Luis Marrero, Jimena Trillo-Tinoco, A. Hamid Boulares, Jann N Sarkaria, Luis Del Valle, Francesca Peruzzi, Augusto Ochoa, Krzysztof Reiss

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Insulin receptor substrate 1 (IRS-1) is a common cytosolic adaptor molecule involved in signal transduction from insulin and insulin-like growth factor I (IGF-I) receptors. IRS-1 can also be found in the nucleus. We report here a new finding of unique IRS-1 nuclear structures, which we observed initially in glioblastoma biopsy specimens and glioblastoma xenografts. These nuclear structures can be reproduced in vitro by the ectopic expression of IRS-1 cDNA cloned in frame with the nuclear localization signal (NLS-IRS-1). In these structures, IRS-1 localizes at the periphery, while the center harbors a key autophagy protein, LC3. These new nuclear structures are highly dynamic, rapidly exchange IRS-1 molecules with the surrounding nucleoplasm, disassemble during mitosis, and require a growth stimulus for their reassembly and maintenance. In tumor cells engineered to express NLS-IRS-1, the IRS-1/LC3 nuclear structures repress autophagy induced by either amino acid starvation or rapamycin treatment. In this process, IRS-1 nuclear structures sequester LC3 inside the nucleus, possibly preventing its cytosolic translocation and the formation of new autophagosomes. This novel mechanism provides a quick and reversible way of inhibiting autophagy, which could counteract autophagy-induced cancer cell death under severe stress, including anticancer therapies.

Original languageEnglish (US)
Article numbere00608
JournalMolecular and Cellular Biology
Volume38
Issue number10
DOIs
StatePublished - May 1 2018

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Insulin Receptor Substrate Proteins
Autophagy
Cell Survival
Neoplasms
alpha Karyopherins
Glioblastoma
Nuclear Localization Signals
IGF Type 1 Receptor
Sirolimus
Starvation
Mitosis
Heterografts
Signal Transduction
Cell Death
Complementary DNA
Maintenance
Insulin
Biopsy

Keywords

  • Autophagy
  • Cellular distribution
  • Fluorescence recovery after photobleaching
  • Glioblastoma
  • Multiprotein complexes
  • Nuclear suborganelle
  • Phase transition
  • Protein binding
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Molecular and structural traits of insulin receptor substrate 1/LC3 nuclear structures and their role in autophagy control and tumor cell survival. / Lassak, Adam; Dean, Mathew; Wyczechowsk, Dorota; Wilk, Anna; Marrero, Luis; Trillo-Tinoco, Jimena; Hamid Boulares, A.; Sarkaria, Jann N; Valle, Luis Del; Peruzzi, Francesca; Ochoa, Augusto; Reiss, Krzysztof.

In: Molecular and Cellular Biology, Vol. 38, No. 10, e00608, 01.05.2018.

Research output: Contribution to journalArticle

Lassak, A, Dean, M, Wyczechowsk, D, Wilk, A, Marrero, L, Trillo-Tinoco, J, Hamid Boulares, A, Sarkaria, JN, Valle, LD, Peruzzi, F, Ochoa, A & Reiss, K 2018, 'Molecular and structural traits of insulin receptor substrate 1/LC3 nuclear structures and their role in autophagy control and tumor cell survival', Molecular and Cellular Biology, vol. 38, no. 10, e00608. https://doi.org/10.1128/MCB.00608-17
Lassak, Adam ; Dean, Mathew ; Wyczechowsk, Dorota ; Wilk, Anna ; Marrero, Luis ; Trillo-Tinoco, Jimena ; Hamid Boulares, A. ; Sarkaria, Jann N ; Valle, Luis Del ; Peruzzi, Francesca ; Ochoa, Augusto ; Reiss, Krzysztof. / Molecular and structural traits of insulin receptor substrate 1/LC3 nuclear structures and their role in autophagy control and tumor cell survival. In: Molecular and Cellular Biology. 2018 ; Vol. 38, No. 10.
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